Pathogenic Variants Role in Arrhythmia Genes Remains Unclear

The study sampled the genetic variants in arrhythmia genes of 2022 individuals

HealthDay News — Potentially pathogenic genetic variants in arrhythmia susceptibility genes are not associated with an abnormal phenotype, according to a study published in the January 5 issue of the Journal of the American Medical Association.

Sara L. Van Driest, MD, PhD, from the Vanderbilt University Medical Center in Nashville, Tennessee, and colleagues examined the clinical phenotypes from electronic medical records (EMRs) for individuals with variants designated as pathogenic in arrhythmia susceptibility genes. Data were included for 2022 individuals recruited for nonantiarrhythmic drug exposure phenotypes from the Electronic Medical Records and Genomics Network Pharmacogenomics project. Three laboratories examined potential pathogenicity in variants in SCN5A and KCNH2, disease genes for long QT and Brugada syndromes. Relevant phenotypes were determined from EMRs.

The researchers identified 122 rare nonsynonymous and splice-site variants in two arrhythmia susceptibility genes in 223 individuals (11% of the cohort). In 63 participants, 42 variants were designated as potentially pathogenic by at least one laboratory, with low concordance across laboratories. Seventeen percent of the 63 variant carriers had an International Classification of Diseases, Ninth Revision code for arrhythmia, compared with 13% of those without variants (P = 0.35). Corrected QT intervals did not differ in variant carriers versus noncarriers among those with electrocardiograms (P = 0.17). In manual review, 35% with designated variants had any electrocardiographic or arrhythmia phenotype; two had corrected QT interval longer than 500 milliseconds.

"In an unselected population, the putatively pathogenic genetic variants were not associated with an abnormal phenotype," the authors write. "These findings raise questions about the implications of notifying patients of incidental genetic findings."